Cerebrovascular Safety of Sulfonylureas: The Role of KATP Channels in Neuroprotection and the Risk of Stroke in Patients With Type 2 Diabetes

Li, Rui; Wang, Haitao; Xu, Baofeng; Chen, Wenliang; Turlova, Ekaterina; Dong, Nan; Sun, Chi; Lu, Yangqingqin; Fu, Hanhui; Shi, Ranran; Barszczyk, Andrew; Yang, Dongzi; Jin, Tianru; Mannucci, Edoardo; Feng, Zhong‐Ping; Sun, Hong‐Shuo

doi:10.2337/db15-1737

Cited by 60 publications

(44 citation statements)

References 70 publications

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“…SUR endow the channel with sensitivity to SUs (Tucker et al 1997). In addition to stimulating the insulin secretion by binding with SUR1 on the membrane of islet beta cell, SUs could also bound to its specific SURs in various other extrapancreatic tissues in the body, causing K ATP channel closure (Tsubouchi et al 2005; Babenko et al 2000; Liu et al 2016). It has been estimated that cardiac and skeletal muscle channels contain Kir6.2 and SUR2A, and smooth muscle K ATP channel are formed by the coupling of SUR2B with either Kir6.2 or Kir6.1 (Liu et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Different sulfonylureas induce the apoptosis of proximal tubular epithelial cell differently via closing KATP channel

Zhang

Zhou

Shen

et al. 2018

Mol Med

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BackgroundSulfonylureas (SUs) are widely prescribed for the treatment of type 2 diabetes (T2DM). Sulfonylurea receptors (SURs) are their main functional receptors. These receptors are also found in kidney, especially the tubular cells. However, the effects of SUs on renal proximal tubular epithelial cells (PTECs) were unclear.MethodsThree commonly used SUs were included in this study to investigate if different SUs have different effects on the apoptosis of PTECs. HK-2 cells were exposed to SUs for 24 h prior to exposure to 30 mM glucose, the apoptosis rate was evaluated by Annexin/PI flow cytometry. Bcl-2, Bax and the ratio of LC3II to LC3I were also studied by western blot in vitro. Diazoxide was used to evaluate the role of KATP channel in SUs-induced apoptosis of PTECs. A Student’s t-test was used to assess significance for data within two groups.ResultsTreatment with glibenclamide aggravated the apoptosis of HK-2 cells in high-glucose, as indicated by a significant decrease in the expression of Bcl-2 and increase in Bax. Additionally, the decreased LC3II/LC3I reflects that the autophagy was inhibited by glibenclamide. Similar but less pronounced change was found in glimepiride group, however, nearly opposite effects were found in gliclazide group. Further, the effects of glibenclamide on apoptosis promotion and the decreased LC3II/LC3I were ameliorated obviously by treatment with 100uM diazoxide. The potential protection effect of gliclazide was also inhibited after opening the KATP channel.ConclusionOur results suggest that, the effects of glibenclamide and glimepiride on PTECs apoptosis, especially the former, were achieved in part by closing the KATP channel. In contrast to glibenclamide and glimepiride, therapeutic concentrations of gliclazide showed an inhibitory effect on apoptosis of PTECs, which may have a benefit in the preservation of functional PTECs mass.

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Section: Discussionmentioning

confidence: 99%

Different sulfonylureas induce the apoptosis of proximal tubular epithelial cell differently via closing KATP channel

Zhang

Zhou

Shen

et al. 2018

Mol Med

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“…Ischemic stroke model was induced by pMCAO as previously described . Briefly, mice were anesthetized with 3.5% chloral hydrate (350 mg/kg, intraperitoneal injection).…”

Section: Methodsmentioning

confidence: 99%

Chinese medicine Tongxinluo capsule alleviates cerebral microcirculatory disturbances in ischemic stroke by modulating vascular endothelial function and inhibiting leukocyte–endothelial cell interactions in mice: A two‐photon laser scanning microscopy study

Liu

Kang²,

He³

et al. 2018

Microcirculation

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“…Ischaemic stroke model was conducted by permanent middle cerebral artery occlusion (pMCAO) as previously described . Briefly, mice were anaesthetized by intraperitoneal injection of 3.5% chloral hydrate (0.35 g/kg).…”

Section: Methodsmentioning

confidence: 99%

The sonic hedgehog pathway mediates Tongxinluo capsule‐induced protection against blood‐brain barrier disruption after ischaemic stroke in mice

Liu

Chang²

2019

Basic Clin Pharma Tox

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Tongxinluo capsule (TXL), a Chinese prescription, has been extensively used for treating ischaemic cerebrovascular diseases in China. Studies have demonstrated that TXL protects the blood‐brain barrier (BBB) after cerebral ischaemia. However, the underlying protective mechanisms are not fully elucidated. Enlightened by the critical role of sonic hedgehog (Shh) pathway in promoting BBB integrity through up‐regulating tight junction (TJ) proteins, we examined whether the Shh pathway could mediate TXL‐induced up‐regulation of TJ proteins and subsequent protection against BBB disruption after stroke. Ischaemic stroke was induced in adult male C57BL/6J mice by permanent middle cerebral artery occlusion (pMCAO). The mice were orally administered TXL (3.0 g/kg) at 1, 3 and 21 hours after stroke. Meanwhile, cyclopamine, a specific Shh pathway inhibitor, was intraperitoneally injected at 1 and 21 hours after stroke. The following parameters were measured at 6 and 24 hours after pMCAO: BBB permeability; TJ proteins including occludin, claudin‐5 and zonula occludens‐1 (ZO‐1); and Shh signalling molecules such as Shh, Patched, Smoothened (Smo) and Gli‐1. Our results showed that TXL protected against BBB disruption at 6 and 24 hours after pMCAO, and cyclopamine partly reversed the protective effect of TXL on BBB. Meanwhile, cyclopamine blocked the effect of TXL–up‐regulated expression of occludin, claudin‐5 and ZO‐1. Moreover, TXL up‐regulated the expression of Shh derived from astrocytes, Patched, Smo and Gli‐1, and thus activated the Shh pathway. And cyclopamine inhibited TXL‐induced activation of the Shh pathway. Thus, our study demonstrates that the Shh pathway mediates TXL‐induced protection against BBB disruption after ischaemic stroke.

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Cerebrovascular Safety of Sulfonylureas: The Role of KATP Channels in Neuroprotection and the Risk of Stroke in Patients With Type 2 Diabetes

Cited by 60 publications

References 70 publications

Different sulfonylureas induce the apoptosis of proximal tubular epithelial cell differently via closing KATP channel

Different sulfonylureas induce the apoptosis of proximal tubular epithelial cell differently via closing KATP channel

Chinese medicine Tongxinluo capsule alleviates cerebral microcirculatory disturbances in ischemic stroke by modulating vascular endothelial function and inhibiting leukocyte–endothelial cell interactions in mice: A two‐photon laser scanning microscopy study

The sonic hedgehog pathway mediates Tongxinluo capsule‐induced protection against blood‐brain barrier disruption after ischaemic stroke in mice

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